Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

Abstract

In various excitable tissues, the hyperpolarization-activated, cyclic nucleotide-gated current (I h ) contributes to burst firing by depolarizing the membrane after a period of hyperpolarization. Alternatively, conductance through open channels I h channels of the resting membrane may impede excitability. Since primary sensory neurons of the dorsal root ganglion show both loss of I h and elevated excitability after peripheral axonal injury, we examined the contribution of I h to excitability of these neurons. We used a sharp electrode intracellular technique to record from neurons in nondissociated ganglia to avoid potential artefacts due to tissue dissociation and cytosolic dialysis. Neurons were categorized by conduction velocity. I h induced by hyperpolarizing voltage steps was completely blocked by ZD7288 (approximately 10μM), which concurrently eliminated the depolarizing sag of transmembrane potential during hyperpolarizing current injection. I h was most prominent in rapidly conducting Aα/β neurons, in which ZD7288 produced resting membrane hyperpolarization, slowed conduction velocity, prolonged action potential (AP) duration, and elevated input resistance. The rheobase current necessary to trigger an AP was elevated and repetitive firing was inhibited by ZD7288, indicating an excitatory influence of I h . Less I h was evident in more slowly conducting Aδ neurons, resulting in diminished effects of ZD7288 on AP parameters. Repetitive firing in these neurons was also inhibited by ZD7288, and the peak frequency of AP transmission during tetanic bursts was diminished by ZD7288. Slowly conducting C-type neurons showed minimal I h , and no effect of ZD7288 on excitability was seen. After spinal nerve ligation, axotomized neurons had less I h compared to control neurons and showed minimal effects of ZD7288 application. We conclude that I h supports sensory neuron excitability, and loss of I h is not a factor contributing to increased neuronal excitability after peripheral axonal injury.

Contribution of hyperpolarization-activated channels to heat hypersensitivity and ongoing activity in the neuritis model

“…The extent of this reduction was considerably less (44.1% reduction after 25 min) compared to the reported effects of ZD7288 on A-fiber neurons in nerve injury models, which is consistent with I h currents being more prominent in this nerve fiber type (Hogan and Poroli, 2008;Gao et al, 2012). For example, using similar protocols, low concentrations (0.05-0.1 mM) of ZD7288 have been shown to rapidly, within 10 min of exposure, reduce A-fiber ongoing activity in nerve injury models (Chaplan et al, 2003;Jiang et al, 2008).…”

Etiology and Pharmacology of Neuropathic Pain

“…This altered activity results from changes in the properties and/or expression of various types of voltage-gated Na + , K + , and Ca 2+ channels (Waxman et al, 1999;Abdulla andSmith, 2001b, 2002;Cummins et al, 2001;Stemkowski and Smith, 2012b;Bourinet et al, 2014;Waxman and Zamponi, 2014;Daou et al, 2016). There are also changes in the function of Na + -K + ATPases (Venteo et al, 2016), intracellular Ca 2+ handling (Hogan et al, 2014;D'Arco et al, 2015;Yilmaz and Gold, 2016;Yilmaz et al, 2017), TRP channels (Basso and Altier, 2017), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Hogan and Poroli, 2008;Emery et al, 2011;Noh et al, 2014;Young et al, 2014).…”

Nerve injury induces a new profile of tactile and mechanical nociceptor input from undamaged peripheral afferents

“…Alternatively (or perhaps even concomitantly), voltage-gated K ϩ channels can also be disrupted after injury (see below). In this particular cellular subtype (largediameter cells), the prominence of I h currents has been a focus of intensive but so far inconclusive studies (Biel et al 2009;Gao et al 2012;Hogan and Poroli 2008;Scroggs et al 1994) about their role in cellular electrical changes detected in axotomized myelinated afferents (A␤/␦).…”